Significance: Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) often affects the kidneys and respiratory system. If left untreated, 80% of patients diagnosed with AAV die within 2 years of disease onset (Mukhtyar et al., 2008). Cyclophosphamide with glucocorticoids is considered the ?standard of care? as induction therapy for those with generalized disease (Jayne et al., 2003), although rituximab plus glucocorticoids has been introduced recently. Cyclophosphamide is given for 3-6 months and remission rates following induction treatment vary from 35 to 93% in GPA and 75 to 89% in MPA (Mukhtyar et al., 2008). There is an unmet medical need for safer, more convenient therapies that are able to rapidly control disease activity and damage. Innovation: Evidence indicates that C5a and its receptor C5aR (also called CD88) are involved in the pathogenesis of ANCA-induced necrotizing crescentic glomerulonephritis (Halbwachs and Lesavre, 2012; Furuta and Jayne, 2013; Kettritz, 2014). CCX168 reduced the severity of disease in an ANCA-induced glomerulonephritis model in human C5aR transgenic mice (Xiao et al., 2014). It substantially reduced both histologic indicators of disease, i.e., glomerular sclerosis and crescents, as well as urinary parameters of disease activity, including hematuria, proteinuria, and leukocyturia. In a clinical trial in patients with AAV, CCX168 plus cyclophosphamide showed higher renal remission and partial renal response rates compared to standard of care (cyclophosphamide plus high dose glucocorticoids). Not only does CCX168 have the potential to be more efficacious than current therapies, but it also has the potential to reduce or even eliminate the use of glucocorticoids in the treatment of these patients. This could reduce or eliminate the well-documented toxicities associated with glucocorticoid use Approach: CCX168 produced effective C5aR blockade in a Phase 1 trial in healthy volunteers. Based on the efficacy results from the first two steps of a clinical trial in patients with AAV, we plan to test the efficacy and safety of CCX168 in 36 additional subjects in this Phase 2 clinical trial. We also plan to conduct a second Phase 2 clinical trial in approximately 45 patients with AAV. The specific aims of this proposal are to evaluate clinical safety and efficacy of CCX168 in patients with AAV; as well as the pharmacokinetic profile. In addition, the effect of CCX168 treatment on biomarkers of AAV disease activity will be evaluated. Activities linked to these specific aims are: 1. Phase 2 placebo-controlled clinical trial in ~60 patients with AAV (CL002_168); and 2. Phase 2 placebo-controlled clinical trial in ~45 patients with AAV (CL003_168).